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BACKGROUND: Ampulla of Vater (AoV) carcinoma is a rare malignancy arising at the junction of intestinal and pancreatobiliary epithelium. Its heterogeneous clinical behavior and histological diversity have hindered therapeutic advances, and the cellular basis of this heterogeneity remains unclear. We aimed to construct a single-cell transcriptomic atlas of AoV carcinoma, with a focus on identifying epithelial subtypes and their interactions with the tumor microenvironment (TME). METHODS: We performed single-cell RNA sequencing on eight primary AoV tumors and four matched normal tissues. Comprehensive clustering and transcriptomic analyses identified cell-type composition, epithelial heterogeneity, and tumor-immune interactions. Findings were validated using deconvolution of bulk RNA-seq data from 62 AoV carcinoma patients. Results Malignant epithelial cells were categorized into four distinct subtypes: Int-Wnt, PB-KRAS, Int-Hypoxia, and Cycling stage. PB-KRAS cells exhibited stem-like transcriptional programs and high genomic instability. Deconvolution analysis of bulk RNA-seq data from the independent AoV cohort revealed that enrichment of the PB-KRAS subtype correlated with tumor recurrence and poor survival. Our immune profiling analysis discovered a significant association between PB-KRAS subtype and GZMK+ CD8+ T cells, which are in a pre-dysfunctional state, alongside SPP1+ macrophages exhibiting immunosuppressive traits. Spatial transcriptome data further supports the immunosuppressive natures of TME around PB-KRAS subtype malignant epithelial cells in AoV carcinoma. CONCLUSIONS: Our study presents a single-cell atlas of AoV carcinoma, highlighting the molecular diversity of malignant epithelium and its association with the immune microenvironment. The PB-KRAS subtype emerges as a stem-like, immunosuppressive tumor state associated with poor prognosis, providing insights for future therapeutic targeting.
Eleven cases of community-acquired Pneumocystis carinii pneumonia occurred between 1979 and 1981 and prompted clinical and immunologic evaluation of the patients. Young men who were drug abusers (seven patients), homosexuals (six), or both (two) presented with pneumonia. Immunologic testing revealed that absolute lymphocyte counts, T-cell counts, and lymphocyte proliferation were depressed, and that humoral immunity was intact. Of the 11 patients, one was found to have Kaposi's sarcoma, and another had angioimmunoblastic lymphadenopathy. Eight patients died. In the remaining three, no diagnosis of an immunosuppressive disease was established, despite persistence of immune defects. These cases of pneumocystosis suggest the importance of cell-mediated immune function in the defense against P. carinii. The occurrence of this infection among drug abusers and homosexuals indicates that these groups may be at high risk for this infection.
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Spleen cells from normal C3H/He or BALB/c mice generate cytotoxic T-lymphocyte (CTL) responses to both trinitrophenyl (TNP)-modified syngeneic cells (TNP-self) and allogeneic cells. In contrast, cells from these strains of mice bearing a syngeneic tumor failed to induce anti-TNP-self-CTL responses, although portions of the same responding cells generated comparable anti-allo-CTL responses to those induced by normal responding cells. Although anti-allo-CTL responses were inducible from only Lyt-2+ T-cell subset of responding cells from normal or tumor-bearing mice, induction of TNP-CTL responses required the participation of L3T4+ T-cell subset as well as Lyt-2+ CTL precursors. In addition, the fact that the addition of concanavalin A-stimulated culture supernatant to cultures of responding cells from tumor-bearing mice resulted in the induction of appreciable anti-TNP-self CTL responses demonstrated the defect of L3T4+ T-cell function in the tumor-bearing state. Such a functional defect was ascribed neither to the loss of L3T4+ T cells nor to the generation of suppressor cells in spleen cells of tumor-bearing mice. It was found on one hand that in vitro stimulation of antigen-presenting cell (APC)-depleted normal responding population with TNP-self prepared from cells of normal or tumor-bearing mice produced comparable anti-TNP CTL responses. On the other hand, APC-depleted responding cells from tumor-bearing mice were unable to induce anti-TNP CTL responses under conditions in which APC-depleted normal responding cells induced an effective TNP-CTL response. These results indicate that selective impairment of L3T4+ T cell-mediated immunity is induced in the tumor-bearing state and that such an impairment is ascribed to the dysfunction of L3T4+ T cells themselves, but not of APC required for the activation of L3T4+ T-cell subset.
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It is a common belief that certain infections occur more frequently in patients with diabetes mellitus than in nondiabetics. In some infections, poor diabetic control is strongly linked. Diabetics comprise 50%-70% of all patients who undergo nontraumatic foot or leg amputations, the overwhelming majority of which are necessitated by infection and necrosis of soft tissue and/or bone. Imputed host defense abnormalities include defective immune responses (e.g., white blood cell function, granuloma formation), peripheral neuropathies, impaired distal arterial supply, and problems in "control" of the diabetic state eventuating in catabolic metabolism. Increased bacterial translocation as a source of the causative bacteria is another potential entry site. Possible virulence factors of the invading organisms include polymicrobial synergism, glycocalyx formation, and inoculum size. Attention to the principles of preventive education, vascular evaluation, diabetes management, and adequate debridement maximize healing potential.
The analysis of progress curves using the integrated rate equation was applied to the adenosine deaminase-catalyzed conversion of adenosine to inosine. Adenosine deaminase was purified from human red blood cells of phenotypes ADA 1, ADA 2, and ADA 2-1. For all three types, no measurable product inhibition by inosine was observed. These results do not confirm the hypothesis that inosine accumulation in purine nucleoside phosphorylase deficiency causes adenosine deaminase inhibition, resulting in a common mechanism for the immune defects related to these two enzyme deficiencies.
A new case of epidermodysplasia verruciformis (EV) is reported in a 35-year-old man characterized by multiple common warts, flat warts, psoriasis-form lesions, and pityriasis-versicolor-(PV) like lesions. There was no familial history, no mental retardation, and no malignant changes. Human papilloma virus type 8 was identified in PV-like lesions. Immunologic studies detected no abnormalities: Delayed skin tests, DNCB sensitization, levels of immunoglobulins, complement components, circulating immune complexes, number of circulating lymphocytes, lymphocyte membrane markers, proliferative responses to mitogens, Ts activity, and Ts subpopulations as detected by monoclonal antibodies were considered to be within normal limits. A treatment with a retinoid aromatic (RO 10-9359) improved the clinical status of the patient and did not modify the immune parameters.
Current nutrition support improves patient outcome in trauma patients. It appears to do so by limiting the adverse effects of specific nutrient or generalized nutrient deficiencies. Immunosuppression, however, continues as a significant clinical problem. This immunosuppression appears to be part of the inflammatory response that accompanies trauma, and in part, to represent the need for conditional nutrients in this setting. Three nutrients that are being evaluated include arginine, uracil as ribonucleic acid and omega-3 polyunsaturated fatty acids. Animal studies report improved immune function. Early clinical trials are reporting improved immune function and patient outcomes.
Mononuclear cells of malnourished children contain diminished activity of phosphoglycerate kinase and pyruvate kinase (PK). The PK activity of these cells correlates well with the percentage of circulating thymus-derived lymphocytes (T-cells). Phytohemagglutinin causes an immediate increase in PK activity of mononuclear cells of malnourished patients. The correlation of PK activity with T-cells and the response of PK activity to phytohemagglutinin are in distinct contrast to observed perturbations of neonatal mononuclear cell metabolism. The relationship of the metabolic alterations to the pathophysiology of the immune system in malnutrition has not yet been defined.
General patterns of tissue injury are recognized as characteristic for certain groups of viruses and certain types of host/virus interactions. Acute viral infections, limited in time and space, tend to be accompanied by florid but brief virus replication cycles in tissues and lesions or signs of disease are largely attributable to the cytolytic effects of the virus on host cells. Chronic or persistent viral diseases tend to have low (or difficult to detect) levels of infectious virus on tissues and the lesions tend to be dominated by inflammation, antiviral immune responses and/or host tissue proliferation. At the cellular level, 3 general categories of response to viral infection are recognized: acute cellular swelling with eventual cytolysis, persistent infection, and transformation (neoplastic) infection. Acute cellular swelling may be accompanied by syncytial giant cell formation and/or viral inclusion bodies. Cells persistently infected with viruses though morphologically normal, are increasingly recognized as functionally deficient and may eventually display degenerative change. Transformation to neoplastic growth can be both benign or malignant in cellular expression. In vivo, the initial neutrophilic inflammatory response to virus-induced cellular necrosis is transient and is rapidly superseded by virus-specific inflammation mediated by both humoral and cellular factors and supplemented by the numerous inflammation amplification pathways. Vasculitis, a common but frequently unappreciated event, may produce nonspecific tissue damage via hemorrhage and ischemia in addition to providing a mechanism for egress of inflammatory factors into the areas of virus-induced cellular damage. During the healing phase, repair by substitution (e.g., fibrosis and scarring) or by proliferation of uninfected replacement cells may dominate sites of viral infection.(ABSTRACT TRUNCATED AT 250 WORDS)
COVID-19 has caused millions of deaths worldwide since 2019. Vaccination has reduced both transmission and disease severity. However, emerging viral variants have weakened vaccine effectiveness, highlighting the need for new antiviral therapies. This study examines how the SARS-CoV-2-Spike protein (SARS-2-S) induces the VSIR-ISX signaling pathway, leading to metabolic disturbances that may worsen disease progression. Using RNA sequencing, we found that SARS-2-S expression in pulmonary cells activates genes involved in tryptophan and arachidonic acid (AA) metabolism, altering bioactive mediators like kynurenine and prostanoids, which are crucial for inflammation and immune responses. Mechanistically, the ACE2-MYD88 pathway, activated by SARS-2-S, enhances the VSIR-ISX axis through NF-κB signaling, driving these metabolic disruptions. Chromatin immunoprecipitation and genome sequencing revealed that ISX, activated via VSIR-MAPK signaling, upregulates enzymes involved in AA metabolism by binding directly to their gene promoters. Notably, disrupting the VSIR-ISX axis using shRNA interference or NF-κB inhibitors effectively mitigated these metabolic disturbances. Our findings suggest that the VSIR-ISX pathway could be a promising therapeutic target for treating COVID-19 by addressing virus-induced metabolic disruptions.
The relationship of virus-induced immunological dysfunction and tumor dissemination was studied using two related tumor-causing leporipoxviruses: malignant fibroma virus (MV) and Shope fibroma virus (SFV). Recombinant viruses, produced by transferring MV's 10.7 kb BamHI C fragment to SFV, replicate in lymphocytes and suppress lymphocyte function in vitro. Those recombinants that replicate in lymphocytes and suppress lymphocyte function in vitro share about 3.5 kb from MV's C fragment. Some recombinants mimic MV in producing immune suppression and disseminated virus infection in vivo. Other recombinants, even some that are highly immunosuppressive in vitro (e.g. R71), only variably induce immune suppression in vivo, and do not cause disseminated disease. A segment of DNA from MV that transfers to Shope fibroma virus almost all of MV's virulence in vivo was identified.
In this review I propose a hypothesis with a number of testable predictions: that the age-dependent decline in T lymphocyte function is largely the result of the accumulation of memory T lymphocytes with over-active plasma membrane calcium pumps. This idea is consistent with much, though not all, of the currently available data. I will start by presenting the evidence that suggested and most clearly supports this idea, then discuss apparently contrary data (some of it still difficult to reconcile with the model), and lastly consider the implications of the model for our understanding of late life development of the T cell immune system.
A detailed immunologic study of three cases of sinus histiocytosis with massive lymphadenopathy (SHML) was performed to better characterize this rare disorder. One patient had prominent cervical lymphadenopathy that regressed spontaneously, whereas the other two patients had persistent cervical lymphadenopathy and recurrent infections. The first patient was otherwise healthy and had normal immunologic studies. One of the latter patients had a relative increase in blood B cells, a decreased level of serum immunoglobulin A (IgA), decreased blood lymphocyte mitogenic responses to multiple mitogens (37-42% of controls), and cutaneous anergy. The other patient with persistent disease also had a relative increase in blood B cells, polyclonal hypergammaglobulinemia, and circulating immune complexes, as well as decreased blood T cells and markedly decreased blood lymphocyte responses to mitogens (12-37% of controls). Immunohistochemical stains of the lymph nodes of the three patients revealed a characteristic phenotype for the sinus histiocytes: S-100 protein, 3/3; CD14 (Leu M3) 3/3; CD11c (Leu M5), 1/1; CD71 (OKT9), 3/3; CD4 (Leu 3a), 2/3; CD1a (OKT6), 1/3; alpha-1-antitrypsin, 3/3; alpha-1-antichymotrypsin, 3/3; CD35 (C3b), 1/1; CD11b (Mo1), 0/3; CD15 (Leu M1), 0/3; HLA-DR, 0/3; and lysozyme, 0/3. This phenotype suggests that the cells of SHML have features of both the Langerhans/interdigitating cell and mononuclear phagocyte lineages. Emperipolesis by the histiocytes of B cells, T cells, and natural killer cells was demonstrated by a double-staining technique. Our findings indicate that patients with SHML may have a variably expressed immunodeficiency that predisposes them to recurrent infections.
Immunotoxins (ITs) consist of cell-reactive ligands coupled to toxins or their toxic subunits. The ligands are usually antibodies, hormones, or growth factors and the toxins are of bacterial or plant origin. In the case of the plant toxin, ricin, its structure consists of a ribosome-inactivating A chain of 32 Kd linked by a disulfide bond to a galactose-specific lectin (B chain) of approximately 30 Kd. The A and B chains of ricin can be separated following reduction and the A chain can then be purified and chemically linked to different ligands to generate a cell-reactive conjugate. Studies using A chain-containing ITs to specifically delete tumor cells, or regulatory cells of the immune system began a decade ago. Initial in vitro experiments were successful and led to further experiments in vivo. However, in vivo studies carried out over the past five years in both animals and humans have demonstrated that the efficacy of ITs or conjugates in vivo is often poor due to problems involving instability of the conjugate, inferior potency, inaccessibility of tumor cells, nonspecific binding to cells other than the target cells, and the survival of antigen-negative mutants. In addition, immune responses against both the ligand and the A chain are usually elicited, precluding repeated therapy. During the past several years, there have been attempts to solve these problems and thereby develop more effective ITs. By analogy with conventional chemotherapeutic agents, it could be predicted that immunotoxins will require many years of study to optimize their construction and therapeutic regimens.(ABSTRACT TRUNCATED AT 250 WORDS)